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Very interesting.... As a matter of fact, we have been observing significant extracellular toxicity of oligomeric Aβ compared to fibrillar in yeast (1).

However, it is rather difficult to imagine that Aβ would be secreted to kill pathogenic cells, as it is a cyto/neurotoxic protein by itself, even though you may consider Aβ more antimicrobial than neurotoxic.

This interesting concept could begin to explain the widespread amyloid response in AD and in prodromal AD. It may also begin to shed some light as to why Aß vaccination has not been a successful treatment approach.

What good news that microbes are becoming acceptable as possible agents in AD. Regarding the proposal of a generic mechanism, “not one based on any particular organism,” surely a prerequisite for the participation of a putative agent in AD, a disease of long duration, is that 1) the agent actually resides permanently in many aged brains and 2) in infected cells it causes the formation of the biomarker molecules of AD brains.

Perhaps it is time for AD researchers to understand that certain microbes can remain long-term in the body, causing slow cumulative damage, i.e., that not all cause merely acute infections and then do a runner (and also that “controls,” too, can harbor a microbe asymptomatically).

The issue covered in this article is very interesting and reconciles many previous data on amyloids in general and on Aβ peptides in particular.

In general, it has been reported that a variant of SAA (serum amyloid A), whose aggregates are involved in a severe form of systemic amyloidosis, aggregates into annular assemblies able to kill bacterial cells following increase of its serum levels in chronic infections (the SAA itself is an acute-phase protein) (1). In addition, recent findings from Charlie Glabe's lab clearly show that the same Aβ raised against amyloid oligomers recognizes oligomers formed by bacterial pore-forming toxins, further underscoring the analogies between amyloids and natural protein oligomers evolved to kill target cells (2).

Apart from this, the possible physiological role of specific amyloids is clearly emerging not only in the microbial world (see the curli, tofi, chaplins, and hydrophobin stories) but also in mammalian cells, as it has clearly been shown by the Balch group in the case of Pme17-favored melanogenesis (reviewed in 3). In this context, the repeatedly reported and experimentally supported significance of the Aβ peptides as vessel sealants alternative to the fibrinogenic pathway in the CNS is of significance (reviewed in 4). Therefore, it is not surprising, but yet highly interesting, that Aβ peptides may be evolved to provide to the organism (possibly not only to the CNS) a further tool to help fight microbial invasion.

Our identification of Aβ as an antimicrobial peptide strongly supports the idea that AD is, in fact, a disease mediated by the innate immune system. However, we urge caution in drawing unsubstantiated conclusions based on our findings. In particular, we feel it is far too premature to consider untried and highly speculative treatment strategies based around the hypothesis that pathogens infecting the brain cause AD. AD is a terminal illness and available treatment options will only modestly slow disease progression, at best. We therefore empathize with the incentive patients and their families feel to embrace a new albeit unproven therapy.

At the same time, there are good scientific arguments why it is clearly premature to consider antimicrobial treatments for AD given our present level of knowledge. Firstly, simply because Aβ is an AMP does not necessarily mean it is accumulating in AD to fight a microbial pathogen. Aβ could be induced in the brain as part of the innate immune system in response to a chronic persistent infection, to a past transient infection, or to non-pathogenic insults that are unrelated to microorganisms. There are more than 30 known autoimmune diseases. Most of these involve inappropriate immune responses but do not appear to involve microbial pathogens.

Second, even if a microbial pathogen is involved, it may only be involved in “jump-starting” the amyloid cascade. The infection may be long gone by the time the clinical symptoms of AD manifest, in which case antimicrobial drugs would have no effect on the disease's progression. Third, if a pathogen is involved, it is unclear what antimicrobial drug would be appropriate since the possible pathogenic agent could be a virus, bacteria, yeast, or other parasite. We don't know which is most relevant at this time, but this knowledge is key if any antimicrobial treatment strategy is to have any chance of success. Fourth, few of the antibiotics and antiviral agents presently available can actually cross the blood-brain barrier.

In summary, with no clear microbial pathogen to target and highly limited numbers of brain-penetrating drugs in any case, it is premature to attempt antimicrobial-based therapies to treat AD. Moreover, antimicrobial treatments based on “best guess” ideas are far more likely to be harmful than beneficial to AD patients since all drugs, and particularly deliberately cytotoxic ones such as antimicrobials, have side-effects. With this said, we strongly believe that the identification of Aβ as an antimicrobial peptide will open up bright new avenues of research. Once the central questions generated by our findings begin to be answered, novel treatments will hopefully arise.